Numerous oral dosage forms are currently commercially available but they do not always meet the convenience of users: tablets for swallowing require the taking of water, gums and tablets for chewing involve use of the teeth.
Many people have difficulties swallowing conventional tablets which are often of non negligible size. The problems linked to the taking of medicaments (breathlessness, suffocation by obstruction of the throat) are often responsible for poor compliance with the dosages, or even a stopping of the treatment. These problems relate in particular to children, elderly persons, patients suffering from deglutition disorders or pathologies affecting saliva secretion.
The orodispersible dosage forms attempt to overcome these disadvantages by their simple mode of administration. By virtue of a rapid disintegration, which is possible in the presence of saliva, the orodispersible tablet is reduced, within a few tens of seconds after its administration, to small size aggregates which are easy to swallow. In the case of the formulation of a dosage form with immediate release of active agent, oral dispersion allows a more rapid availability in the body compared with the dosage forms to be swallowed by increasing the surface area for exchange with physiological fluids. An increased bioavailability of the active agent results therefrom.
Oral dispersibility does not correspond to a single phenomenon. The mechanism of disintegration is thought to have several origins, which are the swelling of a disintegrating agent in the presence of saliva, the development of a capillary network promoted by the presence of pores in the tablet, the tendency for the particles to return to their initial form, the heat released by the wetting of the constituents which increases the air pressure, and the repulsive force between the particles in contact with water. Regardless of the theory involved, the penetration of water is the first phase of the disintegration. The constituents of the orodispersible tablets should therefore promote it or at least not hinder it. In terms of formulation and manufacture, this therefore involves finding a compromise between the physical characteristics of the tablet and the chemical properties of the excipients.
Numerous rapidly dissolving dosage forms are described in the prior art. U.S. Pat. No. 5,464,632 describes a technology based on the film-coating of the active ingredient, which is intended not only to mask the taste of the active molecules but also to create an insoluble coating enhancing the rate of disintegration of the tablet. Indeed, the solubilization of the excipients at the surface constitutes a brake on the penetration of water into the tablets by increasing the viscosity of the incoming liquid. The formula uses a diluent (polyols), a disintegrating agent (crosslinked polyvinylpyrrolidone) and lubricants and customary adjuvants.
The document PCT/FR00/00495 (WO 00/51568) describes the use of hydrophobic lubricants whose negative action on the penetration of water is compensated by the use of a permeabilizing agent such as silica, in order to increase the affinity of the tablets for water. The formula also comprises a diluent and a disintegrating agent.
Document WO 00/57857 describes, for its part, the use of an effervescent agent coupled with a disintegrating agent so as to enhance the disintegration in the mouth. The formula comprises, in addition, a diluent which is not directly compressible.
Finally, the document FR 98/09221 (FR 2,781,152) describes a technology based on the synergy between a disintegrating agent and a type C acrylic polymer which leads to a considerably enhanced rate of disintegration.
All these technologies have in common the use of at least one disintegrating agent also called “superdisintegrant”. This term groups together compounds whose disintegrating power is high. Among the most efficient, there are in particular KOLLIDON® CL (crosslinked polyvinylpyrrolidone marketed by BASF), EXPLOTAB® (carboxymethylated starch marketed by PENWEST), and AC DI SOL® (crosslinked carboxymethylcellulose sodium marketed by FMC). This superdisintegrant agent is essential in the formulation of orodispersible tablets, and should be used together with a direct compression excipient.
The formulator is then forced to prepare physical mixtures of different excipients necessary for the formulation of orodispersible tablets. However, the physical mixtures impose strict constraints on their production and their handling to ensure homogeneity of the mixture and the absence of demixing, properties which are essential in practice for obtaining tablets of constant quality, and these mixtures do not make it possible to prepare tablets of variable hardness as a function of the intended application. Indeed, the results obtained with such mixtures give rise to tablets of very high hardness, completely unsuitable for a rapid disintegration in the buccal cavity.